The HIV protease is a leading candidate for targeted antiviral drug design because inhibition of this enzyme results in production of non-infectious virions. We are investigating the molecular structure and dynamics of the HIV-1 protease complexed with highly potent and specific inhibitors of the viral enzyme. In addition, we are measuring the protonation states and pKa's of its catalytic aspartyl residues, and its interactions with solvent molecules. Similar studies of the free protease are also underway. This work is the first comprehensive biophysical characterization of the HIV-1 protease and protease/inhibitor complex in solution.